This invention relates to a series of novel imidazolidin-4-one derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following co-pending patent applications: PCT international patent application number PCT/IB97/00675, which designates the United States and was filed on Jun. 11, 1997; U.S. provisional patent application Ser. No. 60/041846 (filed Apr. 9, 1997); U.S. provisional patent application Ser. No. 60/031862 (filed Nov. 27, 1996); U.S. provisional patent application Ser. No. 60/028881 (filed Oct. 17, 1996); PCT international patent application number PCT/IB97/00584, which designates the United States and was filed on May 22, 1997; U.S. patent application Ser. No. 08/653,786 (filed May 28, 1996); PCT international patent application publication number WO 96/40142, which designates the United States and was published on Dec. 19, 1996; PCT international patent application publication number WO 97/13771, which designates the United States and was published on Apr. 17, 1997; PCT international patent application publication number WO 95/23141, which designates the United States and was published on Aug. 31, 1995; U.S. provisional patent application number 60/020696 (filed Jun. 27, 1996); International Patent Application PCT/US92/11292, which designates the United States and was published on Jul. 22, 1993 as WO 93/14085; U.S. Patent 4,876,259, which issued on Oct. 24, 1989; International Patent Application PCT/IB95/00189, which designates the United States and was filed on Mar. 20, 1995; U.S. patent application Ser. No. 08/236,743, which was filed on Apr. 29, 1994.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). The compounds of the present invention exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents.